PROJECT SUMMARY/ABSTRACT Glaucoma, the leading cause of irreversible blindness in the United States and worldwide, remains a major global public health concern. Primary open-angle glaucoma (POAG), age-dependent and intraocular pressure (IOP)-related neurodegeneration of the optic nerve comprises 74% of all types of glaucoma. Glaucoma-related visual loss, even in the presence of normal visual acuity, can lead to significant functional visual impairment and substantial secondary risks to health including depression, falls and motor vehicle accidents. Approximately 3% percent of the world population aged 40 years and older has glaucoma. Worldwide, women comprise 59% of those affected by glaucoma, due in large part to their greater longevity. Women are also at risk for visual loss from glaucoma because they are 24% less likely to be treated for this condition, and some data suggest that women report greater functional loss from glaucoma than men. These sex differences underscore the importance of investigating sex-specific risk factors for glaucoma. To that end, this application builds on a conceptual model and preliminary epidemiological data to explore the novel idea that early loss of estrogen might contribute to early aging of the optic nerve in women and thereby increase women's risk of developing glaucoma. Clinical, epidemiological, and basic science studies indicate that estradiol has neuroprotective effects on the optic nerve. The training and research proposals in this application are aimed at fostering the career path of an independent clinician-scientist who will lead a scholarly program of research that examines factors associated with optic nerve aging and the role of sex steroid hormones, particularly estradiol, in the degeneration of the optic nerve and risk for glaucoma. A proposed five-year program of training and research includes: 1) applying MPH-level training in epidemiological and biostatistical methods to examine the impact of early oophorectomy on glaucoma risk in a large epidemiological cohort study of the health consequences of oophorectomy; and 2) applying training in epidemiologic methods, biostatistics, clinical imaging and sex steroid hormones to a mechanistic, translational study aimed at comparing measures of optic nerve aging, as indexed by thinning of the retinal nerve fiber by optical coherence tomography and decreased light sensitivity by visual field testing in women who underwent early oophorectomy and age-matched controls. This work will guide further research in early glaucoma screening and treatment of women with early natural menopause (approximately 6% of women) and early bilateral oophorectomy (37% of women who undergo bilateral oophorectomy). This training and line of research will provide a foundation for future studies investigating the effects of aromatase inhibitors, selective estrogen receptor modulators and other anti- estrogen treatments on the optic nerve. More broadly, this work serves as a foundation for a future line of investigations into sex-differences and non-hormonal mechanisms of optic nerve aging and risks for glaucoma.